FDA Approves Encorafenib With Cetuximab and mFOLFOX6 for Metastatic CRC

The treatment of metastatic colorectal cancer (mCRC) with a BRAF V600E mutation has been updated with the FDA’s approval of encorafenib (Braftovi; Array BioPharma Inc) with cetuximab and the modified FOLFOX-6 (mFOLFOX6) chemotherapy regimen.¹ This combination received accelerated approval on December 20.

CRC is the second most common cause of cancer deaths in men and women combined,² with mCRC occurring in approximately 20% of patients with stage IV disease.³ Approximately 5% to 9% of all patients with CRC have BRAF V600E mutation,⁴ and prior to this approval they could be treated with encorafenib in combination with either cetuximab or panitumumab. This approval for metastatic CRC adds mFOLFOX6, which includes the drugs leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin,⁵ to the combination for these patients.

The combination of encorafenib with cetuximab and mFOLFOX6 can be used to treat metastatic colorectal cancer | Image credit: Sebastian Kaulitzki - stock.adobe.com

The approval comes as a result of the results of the BREAKWATER (NCT04607421) trial, a phase 3 trial that aimed to evaluate encorafenib plus cetuximab taken alone or together with standard chemotherapy to assess its efficacy in patients with mCRC with the BRAF V600E mutation.⁶ The trial was active-controlled, open-label, and multicenter. None of the participants could have had treatment for mCRC with the BRAF V600E mutation prior to the study.¹

Patients were eligible for the study if they were 16 years or older, had confirmed stage IV CRC with a BRAF V600E mutation, had prior systemic treatment in a metastatic setting, had adequate organ function, had measurable disease, and had a Eastern Cooperative Oncology Group Performance Score of 0 to 1. Patients who had tumors that were locally confirmed, had active bacterial or viral infections within 2 weeks of treatment, or had symptomatic brain metastases were excluded from the study.⁶

All participants were split into 3 groups, where they received either encorafenib plus cetuximab, encorafenib plus cetuximab with chemotherapy, or chemotherapy alone. Encorafenib was taken orally once per day in both groups that received the medication, with cetuximab received every 2 weeks. mFOLFOX6 and FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) were received every 2 weeks in the chemotherapy groups whereas CAPOX (capecitabine and oxaliplatin) was received every 3 weeks for those in the chemotherapy group receiving the treatment. Disease progression, unacceptable toxicity, loss to follow-up, consent withdrawal, or death were all reasons given for the cessation of the treatment.

Objective response rate (ORR) was the primary outcome measured for this trial. This was assessed by assessing the efficacy in the first 110 patients who were randomized to each arm and measured by a blinded review. Patients in the encorafenib with cetuximab and mFOLFOX6 arm had an ORR of 61% (95% CI, 52%-70%) compared with the control arm who had an ORR of 40% (95% CI, 31%-49%). The duration of response was a median of 13.9 months (95% CI, 8.5–not estimable) in patients in the treatment arm compared with 11.1 months (95% CI, 6.7-12.7) in the control arm. The BREAKWATER trial remains ongoing and final calculations of progression-free survival and overall survival have yet to be formally assessed.

Adverse reactions included nausea, rash, fatigue, peripheral neuropathy, vomiting, abdominal pain, decreased appetite, pyrexia, and hemorrhage, all of which were reported in 25% or more of patients. The most common adverse reactions at grade 3 or 4 were increased lipase and decreased neutrophil count, both of which were reported in 20% or more patients reporting grade 3 or 4 events.

References

1. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. News release. FDA; December 20, 2024. Accessed December 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf
2. Key statistics for colorectal cancer. American Cancer Society. Updated January 29, 2024. Accessed December 20, 2024. https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html
3. Ni Y, Liang Y, Li M, et al. The updates on metastatic mechanism and treatment of colorectal cancer. Pathol Res Pract. 2023;251:154837. doi:10.1016/j.prp.2023.154837
4. Strategies for the management of relapsed/refractory metastatic colorectal cancer: from landmark trials to precision medicine. AJMC^®. July 11, 2024. Accessed December 20, 2024. https://www.ajmc.com/view/strategies-for-the-management-of-relapsed-refractory-metastatic-colorectal-cancer-from-landmark-trials-to-precision-medicine
5. Modified FOLFOX-6. National Cancer Institute. Accessed December 20, 2024. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/modified-folfox-6
6. A study of encorafenib plus cetuximab with or without chemotherapy in people with previously untreated metastatic colorectal cancer. ClinicalTrials.gov. Updated December 17, 2024. Accessed December 20, 2024. https://clinicaltrials.gov/study/NCT04607421